Process and intermediates for the preparation of pyroxasulfone, fenoxasulfone and various sulfone analogs of 5,5-dimethyl-4h-1,2-oxazole

Abstract

The invention relates to a process for preparing immediate precursors for pyroxasulfone and fenoxasulfone preparation of the formula (I). The process comprises a bromination of a benzylic position without light irradiation, followed by thoination, which substitutes the bromine atom and after the protecting group is removed, and the revealed thiol or thiolate reacts with a substituted isoxazoline bearing a leaving group at the 3-position. Alternately, the pyroxasulfone or fenoxasulfone immediate precursor is synthesized from arylmethyl bromide by forming a carbon-sulfur bond at the 3-position of a 2-isoxazoline through displacement of a leaving group at the 3-position by an appropriate thionating reagent. The resulting adducts, which is a S-protected 3-thio-2-isoxazoline, may be treated with base to remove the protecting group, to reveal a thiol or thiolate which may subsequently react with the arylmethyl bromide to form the Pyroxasulfone or Fenoxasulfone immediate precursor.

1 . A process for preparing compounds of the formulae (I) or (I′) 
       
         
           
           
               
               
           
         
         which comprises the following steps: 
         a) bromination of a starting material selected from the following compounds: 
       
       
         
           
           
               
               
           
         
         to obtain the following compounds: 
       
       
         
           
           
               
               
           
         
       
       respectively;
 b) thionation of the resulting compound of step a with a thionating agent to obtain the following compounds: 
 
       
         
           
           
               
               
           
         
       
       respectively
 wherein Y is a protecting group; 
 c) substitution of the resulting thiol or thiolate created from a formulae (II) or (II′) compounds of step b with an 2-isoxazoline moiety to yield the compound of formula (I). 
 
     
     
         2 . A process according to  claim 1 , wherein the thionating agent is selected from a group consisting of: dimethyl thioformamide, thiosulfate salts, dithiooxamide, alkyl xanthate salts, thiobenzamide, N-substituted thiourea and thioacetate salts. 
     
     
         3 . A process according to  claim 1 , wherein the process is carried out in an organic solvent selected from a group consisting of: aliphatic alcohols such as MeOH, EtOH, iPrOH, MeCN, DMF, NMP, DMSO, ethylene or propylene carbonate, DMA, cyclic ethers such as 1,4-dioxane or THF, and aqueous mixtures thereof or water itself. 
     
     
         4 . A process according to  claim 1 , wherein the process is carried out at a temperature of 0° C. to 100° C. 
     
     
         5 . A process according to  claim 4 , wherein the process is carried out at a temperature of 20° C. to 50° C. 
     
     
         6 . A process according to  claim 1 , further comprising the step of an oxidation and thereby obtaining pyroxasulfone or fenoxasulfone: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A process for preparing a compound of formulae (III) or (III′) 
       
         
           
           
               
               
           
         
         which comprises a brominating compounds of formulae (IV) or (IV′), respectively: 
       
       
         
           
           
               
               
           
         
         with a brominating reagent in the absence of light irradiation. 
       
     
     
         8 . A process according to  claim 7 , wherein the bromination reagent is selected from a group consisting of: Br 2 , HBr/H 2 O 2 , N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin. 
     
     
         9 . A process according to  claim 7 , wherein the process is carried out in an organic solvent selected from a group consisting of: chlorinated solvents like CH 2 Cl 2 , 1,2-dichloroethane, CHCl 3 , CCl 4 , ethylene or propylene carbonate, MeCN, water or mixtures thereof. 
     
     
         10 . A process according to  claim 6 , wherein the process is carried out at a temperature of 0° C. to 100° C. 
     
     
         11 . A process according to  claim 6 , wherein the process is carried out at a temperature of 20° C. to 50° C. 
     
     
         12 . A process for preparing pyroxasulfone or fenoxasulfone immediate precursors of formulae (I) or (I′) and various sulfone analogs of 5,5-dimethyl-4H-1,2-oxazole, which comprises the following steps:
 d) reacting an isoxazole of Formula (V) with a thionating reagent to create an S-substituted thioisoxazole of Formula (VI); 
 
       
         
           
           
               
               
           
         
         wherein X is a leaving group and Y is a protecting group; 
         e) substitution of the resulting thiol or thiolate created from formula (VI) compounds of step d with arylmethyl-bromide compounds of formula (VII) to yield the compound of formula (VIII) 
       
       
         
           
           
               
               
           
         
       
     
     
         13 . A process according to  claim 12 , wherein pyroxasulfone or fenoxasulfone immediate precursors are S-protected 3-thio-2-isoxazoline and are treated with a base to remove the protecting group, revealing a thiol or thiolate group: 
       
         
           
           
               
               
           
         
         wherein Y is a protecting group and X is a leaving group. 
       
     
     
         14 . A process according to  claim 13 , wherein the pyroxasulfone or fenoxasulfone immediate precursors with a thiol or thiolate group are subsequently react with the arylmethyl bromide to form the pyroxasulfone or fenoxasulfone immediate precursor: 
       
         
           
           
               
               
           
         
         wherein Ar is aryl, Y is a protecting group and X is a leaving group. 
       
     
     
         15 . A process according to  claim 12 , further comprising the step of an oxidation and thereby obtaining pyroxasulfone or fenoxasulfone: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A process according to  claim 13 , further comprising the step of an oxidation and thereby obtaining pyroxasulfone or fenoxasulfone: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A process according to  claim 14 , further comprising the step of an oxidation and thereby obtaining pyroxasulfone or fenoxasulfone: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A process according to  claim 2 , further comprising the step of an oxidation and thereby obtaining pyroxasulfone or fenoxasulfone: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A process according to  claim 3 , further comprising the step of an oxidation and thereby obtaining pyroxasulfone or fenoxasulfone: